{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:40Z","timestamp":1792790320298,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,1]]},"group-title":"Neuroscience","reference-count":66,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01-AG085634, RF1-AG056306, RF1-AG095193, P30-AG062429, P30CA014195, S10-OD023689 and U19-AG023122"],"award-info":[{"award-number":["R01-AG085634, RF1-AG056306, RF1-AG095193, P30-AG062429, P30CA014195, S10-OD023689 and U19-AG023122"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"name":"California Institute for Regenerative Medicine","award":["DISC0-17507 and DISC4-19291"],"award-info":[{"award-number":["DISC0-17507 and DISC4-19291"]}],"id":[{"id":"https:\/\/ror.org\/033m8b439","id-type":"ROR","asserted-by":"crossref"}]},{"name":"BrightFocus Foundation","award":["A2019562S and A2022024F"],"award-info":[{"award-number":["A2019562S and A2022024F"]}],"id":[{"id":"https:\/\/ror.org\/03cvfxv40","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Live like Lou Foundation"},{"name":"Theodor Koerner Fonds"},{"name":"L'Oreal Austria\/OeUK\/OeAW"},{"name":"Freedom Together Foundation"},{"name":"Dolby Foundation"},{"name":"American Federation for Aging Research","award":["30376715"],"award-info":[{"award-number":["30376715"]}],"id":[{"id":"https:\/\/ror.org\/000r61a05","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>Metabolic alterations and dysregulated alternative RNA splicing are central layers of Alzheimer\u2019s disease (AD) pathogenesis, yet whether and to what extent these changes are mechanistically linked in adult human neurons in the aging brain remains unclear. To assess this, we generated induced neurons (iNs) by direct conversion of fibroblasts from sporadic AD patients and age-matched control donors. Fibroblast-derived iNs retaining donor-specific aging signatures have been shown to display several AD-related phenotypes. Metabolomic analysis revealed that AD iNs divert citrate toward ATP-citrate lyase (ACLY)-dependent citrate-to-acetyl-CoA flux, which drives increased nuclear levels of the high-energy metabolite acetyl-CoA. Acetyl-proteomics showed that acetyl-CoA accumulation leads to widespread hyperacetylation of RNA-binding proteins (RBPs) and splice regulators, suggestive of a direct mechanistic link between a metabolic shift and RNA processing. Indeed, single-cell long-read RNA sequencing identifies splicing alterations in AD-relevant transcripts whose isoform usage mirrors changes observed in post-mortem AD cortex samples. Subcellular acetyl-CoA imaging reveals that inhibition of ACLY enzymatic activity selectively reduces nuclear acetyl-CoA levels, and further improves citrate metabolic flux, normalizes RBP acetylation, and re-establishes a normal neuronal splicing landscape in AD iNs. Together, these findings reveal a nuclear acetyl-CoA-RNA processing axis that links age- and disease-related metabolic alterations to alternative splicing dysregulation in AD, and identify neuronal nuclear acetyl-CoA production as a causal and reversible node for restoring metabolic and RNA homeostasis in aging human AD neurons.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Sporadic Alzheimer\u2019s disease (AD) patient-derived directly induced neurons (iNs) shift metabolism toward nuclear acetyl-CoA production via ATP-citrate lyase (ACLY).<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Elevated nuclear acetyl-CoA causes hyperacetylation of RNA-binding proteins (RBPs).<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Patient iNs show pathogenic RNA splicing patterns similar to post-mortem AD brains.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Inhibition of ACLY normalizes neuronal acetyl-CoA metabolism and restores RNA splicing homeostasis.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.26.754222","type":"posted-content","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:25:19Z","timestamp":1790889919000},"source":"Crossref","is-referenced-by-count":0,"title":["Nuclear acetyl-CoA accumulation drives reversible RBP hyperacetylation and transcriptome-wide splicing shifts in age-equivalent Alzheimer\u2019s disease neurons"],"prefix":"10.64898","author":[{"given":"Larissa","family":"Traxler","sequence":"first","affiliation":[{"name":"Department of Neurosciences, University of 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Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Herdy","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Dzieciatkowska","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Reisz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayk","family":"Petrosyan","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California San Diego, La Jolla, CA, USA"},{"name":"Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cat","family":"Siler","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California San Diego, La Jolla, CA, USA"},{"name":"Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin C.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Gorostieta-Salas","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, 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Available from: https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC9833817\/","DOI":"10.1038\/s43587-022-00290-0"},{"issue":"41","key":"2026100603301305000_2026.09.26.754222v1.4","doi-asserted-by":"crossref","first-page":"16562","DOI":"10.1073\/pnas.1310249110","article-title":"U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer\u2019s disease","volume":"110","year":"2013","journal-title":"PNAS [Internet"},{"key":"2026100603301305000_2026.09.26.754222v1.5","doi-asserted-by":"crossref","first-page":"1237874","DOI":"10.3389\/fnmol.2023.1237874","article-title":"Analyzing alternative splicing in Alzheimer\u2019s disease postmortem brain: a cell-level perspective","volume":"16","year":"2023","journal-title":"Front Mol Neurosci [Internet"},{"key":"2026100603301305000_2026.09.26.754222v1.6","doi-asserted-by":"crossref","unstructured":"Yang M , Ke Y , Kim P , Zhou X . ExonSkipAD provides the functional genomic landscape of exon skipping events in Alzheimer\u2019s disease. Brief Bioinform [Internet]. 2021 Sep;22(5). 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The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun [Internet]. 2011 [cited 2026 Apr 20];2(1). Available from: https:\/\/pubmed.ncbi.nlm.nih.gov\/21427723\/","DOI":"10.1038\/ncomms1255"},{"key":"2026100603301305000_2026.09.26.754222v1.13","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws013"},{"key":"2026100603301305000_2026.09.26.754222v1.14","doi-asserted-by":"crossref","unstructured":"Ronowska A , Szutowicz A , Bielarczyk H , Gul-Hinc S , Klimaszewska-\u0141ata J , Dy\u015b A , et al. The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain. Front Cell Neurosci [Internet]. 2018 Jun;12:169. Available from: https:\/\/pmc.ncbi.nlm.nih.gov\/articles\/PMC6052899\/","DOI":"10.3389\/fncel.2018.00169"},{"issue":"9","key":"2026100603301305000_2026.09.26.754222v1.15","first-page":"15","article-title":"Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer\u2019s patients","volume":"28","year":"2021","journal-title":"Cell Stem Cell [Internet"},{"issue":"6","key":"2026100603301305000_2026.09.26.754222v1.16","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.stem.2015.09.001","article-title":"Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects","volume":"17","year":"2015","journal-title":"Cell Stem Cell [Internet"},{"key":"2026100603301305000_2026.09.26.754222v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2022.04.018"},{"key":"2026100603301305000_2026.09.26.754222v1.18","doi-asserted-by":"crossref","unstructured":"Huh CJ , Zhang B , Victor MB , Dahiya S , Batista LFZ , Horvath S , et al. Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts. Elife [Internet]. 2016 Sep;5. 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